Focal segmental glomerulosclerosis (FSGS) occurs in an idiopathic form and in association with HIV infection, both of which are more common among African-Americans (AA). The pathogenesis of FSGS remains an unknown and no effective therapy has been demonstrated. We hypothesize that a gene or genes, present in people of African descent, predisposes to FSGS following exposure to particular environmental factors such as HIV infection. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 200 AA with FSGS and 210 intravenous drug users who have been infected with HIV for at least eight years but retain normal kidney function. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, 258 cases and controls have been genotyped for 22 diallelic candidate genes. Two polymorphic sites in the promoter and first exon of the transforming growth factor beta 1(TGFb1) gene have been shown by this study to be associated with the FSGS phenotype. Analysis of the TGF(TGFb1) alleles provides evidence that the wildtype (ancestral) haplotype is associated with increased risk of FSGS, possibly by the up-regulation of TGF beta 1 protein. The alu insertion/deletion mutation in the angiotensin converting enzyme gene ACE is also associated with FSGS (p=0.001). As there are more than 70 identified SNPs in the ACE gene, it is not possible to discern if this mutation is itself affecting the causal pathway of the disease or if the insertion is in linkage disequilibrium with an as yet undetected susceptibility locus. We are currently using haplotype analysis and sequence analysis to resolve this uncertainty.